The long-term goal of the research is to study the mechanisms by which cardiac output and regional blood flows are regulated in response to alterations in energy requirements of perfused tissues. Present evidence suggests that the increase in cardiac output that occurs during hypoxia is causally related to dephosphorylation in the tissue. Our recent experiments indicate that like hypoxia, acute administration of oxythiamine increases cardiac output and left ventricular dP/dt. Oxythiamine is a competitive inhibitor of thiamine, a coenzyme required for decarboxylation of pyruvate and alpha-ketoglutarate. This decrease in tricarboxylic acid cycle activity is expected to reduce ATP production. Experiments are proposed in this grant application to study whether the hemodynamics effects of oxythiamine are associated with tissue dephosphorylation. We will study the changes in systemic hemodynamics (cardiac output, heart rate, aortic blood pressure, total peripheral vascular resistance, and left ventricular dP/dt and dP/dt/P), regional blood flows by radioactive microspheres, and tissue metabolism (lactate, pyruvate, alpha-ketogluterate, oxygen consumption, adenine nucleotides and adenosine) after acute, subacute and chronic administrations of oxythiamine in chronically instrumented conscious dogs. The potential roles of the sympathetic nervous system and renin-angiotensin-aldosterone system in mediating the hemodynamic responses to oxythiamine will be studied by measuring plasma catecholamines, plasma renin activity, plasma aldosterone and aldosterone secretion rate, and by administering sympathetic and angiotensin blocking agents. In addition, changes in baroreceptor sensitivity and left ventricular function will be studied during chronic thiamine deficiency. The overall purposes of the study are: 1) to determine the mechanisms by which oxythiamine produces circulatory stimulation, and 2) to investigate the pathophysiology of beriberi heart failure. This elucidation of the complex metabolic regulation of the circulation will provide us with a guide for treatment of some kinds of heart failure.